Nature or Nurture

Marianne Berwick, PHD, MPH

Cutaneous melanoma is the most lethal form of skin cancer, killing about one person per hour in the US. Its incidence has risen dramatically worldwide during the past five decades, with concomitant increases in mortality. However, mortality has decreased recently in some developed countries, including Australia, Canada, and the US, presumably owing partly to earlier detection and treatment of the disease, when it is usually curable.

While increased awareness of melanoma has helped make this possible, some important, controversial questions about the disease remain unanswered. First, while considerable research has linked melanoma to sun exposure, surprisingly substantial ecological evidence also indicates that, once diagnosed, its prognosis is better in areas with high ground-level ultraviolet radiation, especially in places with higher incidence rates. Indeed, research has shown that as melanoma incidence in the population increases, average prognosis improves. (Figure 1). Armstrong1 (2004) showed that there was a general relationship between melanoma incidence and survival rates from the mid-1980s on in 24 populations, and that the survival rates increased along with incidence in the US National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) data between the mid-1970s and the early 1990s.

Why this is so has not been fully answered, but Armstrong proffered three possible explanations: that melanoma is detected earlier in higher incidence populations (perhaps because of greater awareness); that treatment is better in higher incidence populations; and that melanoma caused mainly by sun exposure is less aggressive than melanoma arising largely in the absence of sun exposure.

Which leads to an even larger, persistently controversial question: Are melanomas caused mainly by sun exposure or by other factors, above all genetics? In 1993, Armstrong and Kricker found that about 65 percent of all melanoma cases can be attributed to ultraviolet (UV) radiation from the sun,2 though some scientists have questioned the findings since then. And do different types of melanomas have different causes? Are some more sun-related, and others mainly due to genetics, or are these two factors often inextricable?

The Impact of UV Radiation

There is no doubt that intermittent, intense sun exposure - the kind that frequently leads to sunburn, for example, on tropical vacations - is associated with the development of many melanomas, while more long-term, cumulative daily solar ultraviolet (UV) exposure is not.3 Why this should be is a puzzle. Something about consistent, less intense exposure seems to "prime" defense mechanisms against melanoma (though not against squamous cell carcinoma, which increases in frequency with cumulative UV exposure), whether by increasing serum vitamin D levels,4 DNA repair capacity,5 or some other mechanism not yet known.

The role of UV radiation — whether obtained from the sun or in tanning salons — and its interaction with genetic factors in melanoma remains to be elucidated. Most investigators believe that some genetically susceptible individuals are at higher risk when they have greater intermittent UV exposure. However, to date, there has not been convincing evidence for interactions between genes and environment in the etiology of melanoma. This is an area of intense study.

Genetic Factors

Pigmentation

A major indicator of melanoma risk is skin color, which is clearly tied to genetic background: In general, individuals with naturally lighter skin are at higher risk for developing melanoma. Those with darker pigmentation, such as Africans, have a low risk, but when they do develop melanoma, it is often a type considered unrelated to sun exposure, called acral lentiginous melanoma (ALM). This type of melanoma occurs mainly on the palms and soles. [For more information on skin cancer in darker-skinned individuals, see "Skin Cancer and Skin of Color".]

Although population incidence and mortality from melanoma vary with latitude (in many white populations, including that of the US, melanoma incidence and mortality rates increase with proximity of residence to the equator), this association is highly modified by the subjects' pigmentary characteristics, which appear to be under genetic control.7 These characteristics are further modified by UV exposure. Therefore, the focus of investigators is on gene-environment interactions.

The MC1R Gene

Melanin, or skin pigment, is necessary for melanoma development. (Albinos, who lack skin pigment, rarely develop melanoma, though they are at greatly increased risk for squamous cell carcinoma.8) Two types of melanin have been identified: Pheomelanin and eumelanin. The former is associated with red hair, freckles and specific "R," or red hair mutations, in the melanocortin-1 receptor gene (MC1R, also known as alpha melanocyte-stimulating hormone receptor) in association with melanoma. The latter, eumelanin, far more common, is associated with a darker phenotype — dark hair, and darker skin that tans easily. Individuals with a preponderance of either type of melanin can develop melanoma, but those with pheomelanin are at higher risk for the disease.9

CDKN2A

In the most clearly genetic cases of melanoma, the risk of developing the disease literally runs in families. Approximately 5-10 percent of melanoma occurs among families with multiple cases. In 20-40 percent of these families, a mutation in the CDKN2A gene occurs on chromosome 9. Normally, CDKN2A codes for a protein called p16 that is an important regulator of the cell division cycle; it stops the cell from synthesizing DNA before it divides, thereby controlling rampant proliferation of cells. When CDKN2A malfunctions, it does not properly code for p16, thereby depriving the skin cell of the normal brake on the cell division cycle and proliferation.

The genetic anomaly occurring in CDKN2A is the major identified mutation in familial melanoma. Another gene, CDK4, related to CDKN2A, as it is also related to the cell cycle, has been shown to have very rare mutations and has been found in only 7 families worldwide. A group of families in the Netherlands have been diagnosed with both melanoma and pancreatic cancer, and this combination has also been ascribed to a mutation in CDKN2A.

Although CDKN2A is the most well-studied mutation in melanoma, it is still very rare.10 Screening tests are available, but the International Melanoma Genetics Consortium has published information about genetic screening,11 coming to the conclusion that genetic testing for CDKN2A is not warranted at this time except as part of a research protocol. Their reasoning is that individuals at high risk for melanoma should be under surveillance by their physician and preferably a dermatologist. Individuals with multiple nevi (moles), particularly atypical nevi, or a family history of melanoma are at high risk and should be seen at least annually for a full-body examination.

Survival with Melanoma

Do genetic factors also affect survival once melanoma has been diagnosed? More than 90 percent of melanomas diagnosed today in the US and Australia are successfully treated by early surgery. However, 10 percent of melanomas have been highly recalcitrant to treatment. In the quest for better understanding, multiple investigators are evaluating the role of genetic factors in survival. While excessive, intermittent sun exposure is an important risk factor for melanoma, it does not appear to be associated with poorer melanoma survival. Thus, genetic factors may be the culprit; it could be that individual melanoma patients with a particular constellation of inherited genetic mutations are those who have increased mortality from the disease. Lemish, et al observed that survival increased with increasing melanoma incidence across several populations12 and suggested that melanoma occurring in association with high ambient sun exposure might be biologically "more benign." Reinforcing this notion, solar elastosis (changes in the skin due to sun exposure) has also been linked to greater melanoma survival.

Given the role of sun exposure in the synthesis of vitamin D and the anti-proliferative and anti-carcinogenic actions of vitamin D, genetic alterations in the gene that controls the vitamin D receptor or related genes might reasonably be associated with poorer survival from melanoma. It may be that individuals who have aggressive melanoma have a different set of genetic mutations from those common in more indolent melanomas.

The genetic factors associated with melanoma progression and survival are still being explored. While genetics in other cancers can be assessed by gene expression analyses from fresh tumor tissue, this is extremely difficult in melanoma, as primary melanomas are so small, and pathologists need all of the lesion in order to diagnose the disease correctly. Another alternative is to measure single nucleotide polymorphisms (SNPs) — either in germline DNA (that which is inherited) or in tumor DNA using the DNA from paraffin-embedded tumors. However, these studies are still few in number and have usually been performed on small numbers of patients that are not usually representative of the general population of melanoma patients. Therefore, they are difficult to interpret so far.

Conclusion

At this point, the role of genetics in melanoma is still unclear. While intense, intermittent sun exposure is clearly important in the etiology of melanoma, its importance for survival is not known. Therefore, one cannot reliably say whether nature or nurture (i.e., behavior) is more important in either the etiology or the progression of melanoma. Hopefully, this uncertainty will continue to spur research to answer these questions.

Dr. Berwick is professor and chief of the Division of Epidemiology and Biostatistics at the University of New Mexico's Department of Internal Medicine and associate director of the Population Science Program, UNM Cancer Center, Albuquerque. She has co-authored over 100 peer-reviewed publications and is a member of the Society for Melanoma Research's Steering Committee and the National Cancer Institute's Subcommittee-A.